Energy expenditure can be measured accurately and precisely under laboratory conditions using either direct or indirect calorimetry; however, these methods are not applicable outside of the laboratory. Methods that have been developed to measure energy expenditure in the free living subject include dietary record, activity monitoring, and heart rate monitoring, but these methods are very dependent on subject compliance and generally not very accurate or precise. In order to reduce the reliance on subject compliance and increase accuracy and precision, we have begun to validate the doubly labeled water method for the measurement of energy expenditure in humans. Water labeled with 18O and 2H is administered by mouth, saliva is collected 4 hours later for the determination of total body water, and urine is collected at 7 to 14 day intervals for the determination of the isotope elimination rates. Because the oxygens in CO2 and H2O are isotopic equilibrium, the difference in the 18O and 2H elimination rates is a measure of CO2 production and hence energy expenditure. The 2H and 18O isotope abundances are measured by differential isotope ratio mass spectrometry. Previous investigators have demonstrated accuracies and precisions of 2 to 6% in small animals, and we have found the method to be similarly accurate and precise in healthy young adults. We propose to further develop and optimize the method for human studies. We will validate the method against indirect calorimetry and/or dietary record in healthy subjects and hospitalized patients to determine the limitations of the method under ideal and nonideal conditions. We will then begin field trials of the method in a number of clinical situations to validate its clinical usefulness and to identify any procedural difficulties. During these trials we will determine the energy expenditure of patients with Crohn's disease, controlled and uncontrolled diabetes, and adolescent obesity as well as healthy elderly subjects. The doubly labeled water method should permit us to address questions of energy expenditure in the free living subject under normal conditions of activity, questions that have been difficult to answer using previously available methods.